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Copy Number Profiles Point to Possible Prognostic Alterations in Liver Cancer Metastases

NEW YORK (GenomeWeb) – A team led by researchers in Germany has tracked down copy number profiles that appear to correspond to poorer-than-usual outcomes in individuals with a form of liver cancer called intrahepatic cholangiocarcinoma (iCCA).

Using genome-wide array comparative genomic hybridization, the researchers searched for informative copy number alterations in 37 primary iCCA samples and more than a dozen matched lymph node metastases. Prior research suggested that lymph node metastases coincided with significantly poorer survival times in iCCA patients, they noted.

The team's findings, published online today in Scientific Reports, highlighted known copy number changes in iCCA, along with previously unappreciated gains involving portions of chromosome 19. Still more gains and losses turned up in the corresponding metastatic samples. And in a cluster of primary tumors from patients with lymph node metastases, the investigators identified copy number alteration-rich tumors coinciding with distinct tumor differentiation characteristics and poorer survival times.

"For the first time, a matched analysis of primary iCCA tumors and their corresponding [lymph node metastases] was performed showing highly similar [copy number alterations] with very specific novel alterations in the [lymph node metastases]," senior author Anja Lachenmayer — a surgery researcher affiliated with Heinrich-Heine University and University Hospital Duesseldorf, and Bern University Hospital — and her colleagues wrote.

"Multiple genes located in the altered regions of our cohort are known to be involved in cancer-associated pathways and have been reported as potential targets for new anti-tumoral treatment strategies," they added, noting that the search led to a "novel molecular subclass with a high amount of [copy number alterations] and a significant association to poor tumor differentiation and poor prognosis."

Starting with 78 formalin-fixed paraffin-embedded tumor samples from 60 iCCA patients, the researchers tossed out cases without available clinical data. They then used aCGH with Agilent oligonucleotide arrays to assess copy number alterations in 37 primary iCCA and 14 matched metastatic tumors. They also profiled mutations in the KRAS and TP53 genes in 18 of the primary and matched tumor sets.

The team's analysis highlighted losses affecting tumor suppressor genes and new recurrent gains involving chromosome 19q, along with a rise in copy number alterations in primary tumors that went on to spawn lymph node metastases compared to cases without lymph node metastases.

Although the lymph node metastases contained some 86 percent of the copy number alterations identified in the corresponding primary iCCA tumors, the researchers reported, they were also prone to accumulating still more gains and losses. For example, they noted that most of the metastatic tumors — 79 percent — had chromosomal gains not found in the corresponding primary tumor, including gains affecting genes from chemokine-signaling and chromosomal stability pathways.

On the other hand, the primary tumors were more apt to contain mutations affecting the TP53 and KRAS genes. The TP53 and KRAS genes turned up in 19 percent of the primary tumors, but only in 6 percent of the metastatic tumors occurring in the lymph nodes.

When the team incorporated survival data for the iCCA patients, it saw reduced survival times in patients who had poorly differentiated primary tumors falling into a cluster marked by frequent copy number alterations and CNVs involving cancer-related genes. In that group, the average survival time was just 13 months, compared with 31 months, on average, in the patients with tumors outside this copy number cluster. 

"This poor prognosis group harbored significantly more CNAs, including chromosomal alterations at 7p, 9p, and 17q that have previously been described to be related to poor tumor differentiation and worse survival in iCCA," the authors wrote.

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